RT Journal Article
SR Electronic
T1 Pharmacological Characterization of AZD5069, a Slowly Reversible CXC Chemokine Receptor 2 Antagonist
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 340
OP 350
DO 10.1124/jpet.114.221358
VO 353
IS 2
A1 Nicholls, David J.
A1 Wiley, Katherine
A1 Dainty, Ian
A1 MacIntosh, Fraser
A1 Phillips, Caroline
A1 Gaw, Alasdair
A1 Mårdh, Carina Kärrman
YR 2015
UL http://jpet.aspetjournals.org/content/353/2/340.abstract
AB In normal physiologic responses to injury and infection, inflammatory cells enter tissue and sites of inflammation through a chemotactic process regulated by several families of proteins, including inflammatory chemokines, a family of small inducible cytokines. In neutrophils, chemokines chemokine (CXC motif) ligand 1 (CXCL1) and CXCL8 are potent chemoattractants and activate G protein–coupled receptors CXC chemokine receptor 1 (CXCR1) and CXCR2. Several small-molecule antagonists of CXCR2 have been developed to inhibit the inflammatory responses mediated by this receptor. Here, we present the data describing the pharmacology of AZD5069 [N-(2-(2,3-difluorobenzylthio)-6-((2R,3S)-3,4-dihydroxybutan-2-yloxy)[2,4,5,6-13C4, 1,3-15N2]pyrimidin-4-yl)azetidine-1-sulfonamide,[15N2,13C4]N-(2-(2,3-difluoro-6-[3H]-benzylthio)-6-((2R,3S)-3,4-dihydroxybutan-2-yloxy)pyrimidin-4-yl)azetidine-1-sulfonamide], a novel antagonist of CXCR2. AZD5069 was shown to inhibit binding of radiolabeled CXCL8 to human CXCR2 with a pIC50 value of 9.1. Furthermore, AZD5069 inhibited neutrophil chemotaxis, with a pA2 of approximately 9.6, and adhesion molecule expression, with a pA2 of 6.9, in response to CXCL1. AZD5069 was a slowly reversible antagonist of CXCR2 with effects of time and temperature evident on the pharmacology and binding kinetics. With short incubation times, AZD5069 appeared to have an antagonist profile with insurmountable antagonism of calcium response curves. This behavior was also observed in vivo in an acute lipopolysaccharide-induced lung inflammation model. Altogether, the data presented here show that AZD5069 represents a novel, potent, and selective CXCR2 antagonist with potential as a therapeutic agent in inflammatory conditions.